California Pacific Currents 2005

CRCLE: New Research Offers Promise for Improved Therapies

At California Pacific's Centers for Research in Clinical Excellence (CRCLE), specialists in several fields have launched new research initiatives while moving established ones forward. CRCLE represents an ongoing effort to relate patient-specific data and outcomes information to the development of improved diagnostic and therapeutic approaches to a number of conditions.

Patients who agree to participate in the programs donate samples of blood or tissue, which are stored for later evaluation. As researchers learn more about the conditions being studied, they will be able to analyze the donated samples, correlate the data with individual patient histories and results, draw conclusions about the most promising treatments, and assess new tests for risk of disease.

"This is research you can use," says Steven Cummings, MD, FACP, who oversees the program. "CRCLE gives patients the opportunity to be part of research that will improve their care and that of their sons and daughters in the future." The new CRCLE projects include bariatric surgery, kidney transplantation, and complex pregnancy; researchers are conducting ongoing projects in breast health and gastroparesis.

Bariatric Surgery Research Aims at Treatments for Several Related Conditions In CRCLE's bariatric surgery project, researchers will track a cohort of patients who have had surgery to assess the procedures' effects on physiological and psychological variables. Bariatric surgery is performed on those who are morbidly obese and at increased risk for diabetes, cardiovascular disease, and other health problems. The procedures either restrict stomach volume or reconfigure anatomy so that the stomach empties lower than normal in the small intestine, deliberately creating a malabsorption syndrome. The operations are almost all done laparoscopically, without major incisions.

The researchers' first goal is to learn about what makes bariatric surgeries successful. They are also interested in the procedures' effects on physiology, including digestive hormones. sleep disorders, sexual functioning, and mood. "We want to understand how each of these surgeries affects a different part of the stomach and its receptors for hormones associated with hunger, satiety, and obesity metabolism," says Dena Bravata, MD, MS. Dr. Bravata, a California Pacific internist, as well as a Stanford health services researcher, is a principal investigator on the project, along with surgeon colleagues Gregg Jossart, MD; John Feng, MD; and Paul Cirangle, MD. "This information could be helpfnl for bariatric patients and for future pharmacological approaches to obesity," Bravala adds.

One intriguing outcome of bariatric surgery is that patients are losing more weight than their physicians had predicted, which has spurred the researchers to look for other causes of weight loss associated with the operations. "That's exciting because people in the future may be able to get those benefits without surgery," she explains.

Bariatric surgery patients reap other benefits as well, For example, diabetes patients typically experience a normalization of blood sugar levels after the surgery that allows them to stop taking diabetes medications. The change has partly to do with restricted calorie diets, but there also may be effects on the hormones associated with the diabetic metabolic syndrome, Bravata says.

RKIVE Project May Lead to Greater Success in Kidney TransplantationThe Bioarchive in Recipients of Kidney Transplants (RKIVE) will establish an archive of blood, serum, and tissue samples from California Pacific patients who have received a kidney transplant. The major goal is to draw correlations between biological markers in the donated samples and treatment outcomes, so that when more is known about organ rejection, patients can have treatments individually tailored to their own physiological responses.

California Pacific's kidney transplantation program is one of the busiest in the nation, performing about 200 procedures a year, so it is a natural place in which to conduct such research, according to Ram Peddi, MD, transplant nephrologist and director of the kidney transplant research program. "We have come a long way with kidney transplants," Peddi says, pointing out that in the early days of the procedure, six out of ten patients lost their transplants due to acute rejection, during which the body's immune cells attack the grafted kidney. "Now, over 95 percent of kidney transplants last more than a year. Rejection rates are much lower; over 90 percent of acute rejection episodes can be treated."

Nevertheless, long-term outcomes are much more problematic, and it is in this area that researchers hope RKIVE data will be helpful, "Over time, a significant number of people lose their grafts due to chronic rejection, an immune process that can take years," Peddi explains.

The RKIVE team will collect and store the samples, and as new technology becomes available they will evaluate several cytokine markers (proteins that help regulate immune response) in serum and urine to see which patients are at highest risk for rejection. Ideally, this information will lead to better treatment options. “As new anti-rejection medications become available, we will see which patients benefit from which drugs so that we can individualize treatment," Peddi says. RKIVE staffers hope to have 300 subjects enrolled within two years.

Biological Factors in Complex PregnancyIn the Cohort of Complex Pregnancy Problems (COMPP) study, researchers will collect blood samples from women planning to deliver their babies at California Pacific who have "complex pregnancies, "which includes conditions such as preterm labor, hypertension (specifically, preeclampsia), diabetes, and autoimmune diseases such as lupus. The goal, as in other CRCLE programs, is to develop a bank of information that can be mined as advances improve diagnostic capabilities for these and related problems. Because up to 10 percent of women have preterm labor problems, the potential applications of such knowledge are significant. COMPP researchers want to enroll 1,500 women over two years.

"This study is designed so that patients will have data collected during their pregnancies that can be matched with biological specimens for retrospective analysis," says Tom Musci, MD, California Pacific's director of perinatal research, who is board-certified in both genetics and maternal-fetal medicine. The data will include information about stress, exercise, medications, herbs, alternative therapies, blood pressure, weight gain, and ultrasound results.

Musci explains that these data and the blood samples will be kept in anticipation of scientific advances that may lead to new diagnostic techniques. The hope is that eventually clinicians will be able to examine women with apparently normal pregnancies and identify biological markers that may portend trouble. According to Steve Cummings, MD, many complications should be preventable with such information. "This will probably be the largest study in the United States to help improve the outcomes of complex pregnancies," he says.

Updates on Ongoing Studies: The Breast Health Study Two CRCLE projects described in last year's Currents have continued to make progress. The Breast Health Study is compiling a databank of mammograms and blood samples that, in combination with new technologies, may help clinicians predict postmenopausal women's risk of developing breast cancer. "All of this will eventually allow us to see if combinations of a woman's breast density, age, family history, and hormone levels will give us an accurate assessment of her breast cancer risk," notes Cummings, who directs the program along with Fred Margolin, MD. Within two or three years, Cummings adds, new compounds will become available that may reduce a woman's risk of developing breast cancer by nearly 70 percent, so it will be critical to identify patients who may benefit. Roughly 15,000 patients have had the breast-density mammograms since 2004 and about 4,000 have given blood samples.

Gastroparesis Study The CRCLE project in gastroparesis, also known as delayed gastric emptying, has collected blood and tissue samples, as well as quality-of-life measures, from 120 patients. "We're continuing to develop new techniques for the evaluation and treatment of gastroparesis, including an electrical stimulator to increase stomach contractions, the use of an injection to paralyze the pylorus (the sphincter [valve] between the stomach and the small intestine), and pyloroplasty (a surgical procedure to enlarge the pylorus) in patients with elevated sphincter pressures,” says William Snape, MD, the program's director.

"We hope that the systematic evaluation of new techniques, combined with other quality-of-life measures and results from the tissue and serum bank, will lead to better treatments,” Snape explains.